我校西南医院邓国宏教授团队在Journal of Hepatology发表研究成果——HBV特异性CD4 T细胞TNF-α/IFN-γ功能谱与慢乙肝患者肝损伤及
发布人:wuph 发布时间:1/9/2020 5:16:31 PM  浏览次数:20342次
【字体: 字体颜色

HBV特异性CD4 T细胞TNF-α/IFN-γ功能谱与慢乙肝患者肝损伤及病毒清除相关
王昊亮 罗恒 万星 谭文婷 邓国宏
 
慢性乙型肝炎病毒(HBV)感染是我国公共卫生健康的重大挑战:HBV感染造成的长期慢性肝脏炎症损伤能导致患者发生肝硬化、肝癌;短期爆发性肝脏炎症损伤能导致患者发生慢加急性肝衰竭;当前治疗手段只能在小部分患者人群中实现病毒清除。作为非溶胞性病毒,HBV感染所引发的免疫应答在肝损伤及病毒清除中起主导作用,而CD4 T细胞在其中所起的具体作用目前知之甚少。
 
陆军军医大学西南医院邓国宏团队发现:HBV特异性CD4 T细胞以TNF-α+细胞为主,该群细胞在高炎症患者中大量活化,加重肝损伤;而TNF-α+细胞向IFN-γ+细胞的分化则利于患者病毒清除,该分化过程伴随着T细胞特化转录因子T-bet、效应分子IL-21的上调。该研究首次揭示HBV特异性CD4 T细胞的不同功能亚群分别参与肝损伤及病毒清除。当前主流观点认为慢性病毒感染T细胞处于耗竭状态,无法有效介导病毒清除。该研究则提示,HBV特异性TNF-α+ CD4 T细胞很可能是处于分化早期T细胞而非耗竭T细胞,其向IFN-γ+ CD4 T细胞分化受阻很可能是患者无法有效清除HBV病毒的重要因素。
 
基于该发现,进一步深入研究HBV特异性TNF-α+ CD4 T细胞向IFN-γ+ CD4 T细胞分化的分子机制,有望找到关键调控靶标,以促使HBV特异性CD4 T细胞应答由肝损伤向病毒清除方向转变。
上述研究成果于2019年9月以论著的形式发表在《Journal of Hepatology》(IF 2018 = 18.946)。
英文摘要:
Abstract
Background & Aims: The role of Hepatitis B virus (HBV)-specific CD4 T cells in patients with chronic HBV infection is not clear. Thus, we aimed to elucidate this in patients with chronic infection, and those with hepatitis B flares. Methods: Through intracellular IFN-γ and TNF-α staining, HBV-specific CD4 T cells were analyzed in 68 patients with chronic HBV infection and alanine aminotransferase (ALT) < 2× the upper limit of normal (ULN), and 28 patients with a hepatitis B flare. HBV-specific HLA-DRB1*0803/HLA-DRB1*1202-restricted CD4 T cell epitopes were identified. Results: TNF-α producing cells were the dominant population in patients’ HBV-specific CD4 T cells. In patients with ALT < 2×ULN, both the frequency and the dominance of HBV-specific IFN-γ producing CD4 T cells increased sequentially in patients with elevated levels of viral clearance: HBV e antigen (HBeAg) positive, HBeAg negative, and HBV surface antigen (HBsAg) negative. In patients with a hepatitis B flare, the frequency of HBV core-specific TNF-α producing CD4 T cells was positively correlated with patients’ ALT and total bilirubin level, and the frequency of those cells changed in parallel with the severity of liver damage. Patients with HBeAg/HBsAg loss after flare showed higher frequency and dominance of HBV-specific IFN-γ producing CD4 T cells, compared to patients without HBeAg/HBsAg loss. Both the frequency and the dominance of HBV S-specific IFN-γ producing CD4 T cells were positively correlated with the decrease of HBsAg during flare. A differentiation process from TNF-α producing cells to IFN-γ producing cells in HBV-specific CD4 T cells was observed during flare. Eight and 9 HBV-derived peptides/pairs were identified as HLA-DRB1*0803 restricted epitopes and HLA-DRB1*1202 restricted epitopes, respectively. Conclusions: HBV-specific TNF-α producing CD4 T cells are associated with liver damage, while HBV-specific IFN-γ producing CD4 T cells are associated with viral clearance in patients with chronic HBV infection.
Key words: Hepatitis B virus; CD4 T cells; Liver damage; Viral clearance; Epitope.
 
 
王昊亮,免疫学博士,陆军军医大学第一附属医院感染病科博士后。
 
 
罗恒,微生物学硕士研究生。
 
万星,陆军军医大学第一附属医院感染病科助理实验师。
 
谭文婷,传染病学博士,陆军军医大学第一附属医院感染病科副主任技师。
 
邓国宏,教授,博导,陆军军医大学西南医院感染病科副主任。教育部“新世纪优秀人才”、军队“科技新星”、重庆市杰青、重庆市“传染病学”学术技术带头人。现任中华医学会肝病学分会委员、全军防生专委会副主委、重庆市医学会感染病专委会副主委。
 

『 发表评论 』
标 题:
用 户 名:
验 证 码:
留言内容: